Inhibition of carbon tetrachloride-induced lipid peroxidation by novel antioxidants in rat hepatic microsomes: dissociation from hepatoprotective effects in vivo.
The ability of two novel antioxidants, U-74,006F and U-78,517G, as well as the known antioxidant N,N'-diphenyl-p-phenylenediamine to inhibit lipid peroxidation induced by carbon tetrachloride (CCl4) was investigated in Aroclor 1254-induced rat hepatic microsomes. All three compounds completely inhibited lipid peroxidation in microsomes as measured by the formation of thiobarbituric acid reactive substances (TBARS). Inhibition of lipid peroxidation was not a function of decreased bioactivation of CCl4, as the compounds did not substantially inhibit benzphetamine N-demethylase activity or covalent binding of [14-C]CCl4 to lipid or protein. Parallel studies examined the hepatoprotective effects of the compounds in vivo. Rats were pretreated with antioxidant or vehicle prior to administration of CCl4 (300 or 600 microL/kg i.p.). Sera were collected 24 h postadministration of CCl4 and analyzed for alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities and total bilirubin. Administration of CCl4 produced elevations in ALT, moderate changes in bilirubin, and no change in ALP activities. Histological examination of CCl4-treated livers revealed lipidosis and centrilobular necrosis. The antioxidants partially improved the clinical chemistry parameters, but had minimal effects on the histological lesion. In contrast to the complete inhibition of lipid peroxidation observed in the in vitro studies, none of the antioxidants markedly protected against CCl4-induced toxicity in vivo.
Wolfgang
G H
GH
Upjohn Company, Kalamazoo, Michigan 49001.
Jolly
R A
RA
Donarski
W J
WJ
Ochoa
R
R
Petry
T W
TW
D000410:Alanine Transaminase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002251:Carbon Tetrachloride / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D002839:Chromans / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects*; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011281:Pregnatrienes / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000975:Antioxidants; D002839:Chromans; D008054:Lipid Peroxides; D010655:Phenylenediamines; D010879:Piperazines; D011281:Pregnatrienes; C066382:U 78517F; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; C004845:N,N'-diphenyl-4-phenylenediamine; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase